The broad theme of this application is to elucidate the biology of antigen presenting cells (APC) in vivo. Professional APC serve as sentinels that alert the immune system to the presence of foreign antigen and are probably the only cells that can initiate T cell responses. Despite this essential role, we know relatively little about the abilities of different APC to initiate and influence immune responses in vivo. Our overall objective is to define the role that different APC play in the generation of various immune responses in animals. We have three specific Aims. The goal of the first Aim is to define which APC can stimulate naive T cells to clonally expand. Our underlying hypothesis is that several different kinds of professional APC can and do participate in the generation of T cell responses. We will examine this hypothesis for both naive CD8 and CD4 T cells and for different lineages and subsets of APC. Our experimental approaches will include testing the ability of different APC to stimulate T cells upon adoptive transfer into mice, visualizing the interactions between specific APC and T cells in situ and determining the effects of depleting specific subpopulations of APC in vivo using new genetic models. The goal of the second Aim is to determine how different APC influence the course and outcome of immune responses. We will examine the hypothesis that stimulation of naive T cells by different APC will lead different outcomes: Tolerance versus response, TH1/TC1 versus TH2/TC2 effector cells, and/or the generation of memory. In addition we will test the hypothesis that the APC requirements to stimulate memory cells are different than for naive T cells. The experimental approaches are similar to Aim 1. The third Aim is based on the finding that APC are lost during the generation of immune responses. The goal of this Aim is to define the mechanisms and consequences of APC loss during immune responses. We hypothesize that this loss of stimulator cells limits the magnitude and duration of immune responses. We further hypothesize that preventing the loss of APC may be useful to boost responses and enhance the efficacy of vaccines. The goals of this Aim are to test these hypotheses and determine the underlying mechanism for the loss APCs.